There is now a body of evidence that metalloproteinases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form inactive complexes with the MP's.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteinases. The available evidence supports that it is the metalloproteinases which are responsible for the degradation of the extracellular matrix of articullar cartillage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase (a newly identified metalloproteinase enzymatic activity) has been identified that provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22).
Therefore metalloproteinases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990).
This invention describes macrocyclic molecules that inhibit aggrecanase and other metalloproteinases. These novel molecules are provided as cartilage protecting therapeutics. The inhibiton of aggrecanase and other metalloproteinases by these novel molecules prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of osteo- and rheumatoid arthritis.
Tumor necrosis factor (TNF) is a cell associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumsatnces including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn's disease (Macdonald T. et al. Clin. Exp. Immunol. 81, 1990, 301)
Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloproteinase or family of metalloproteinases, hereafter known as TNF-convertases (TNF-C), as well as other MP's are capable of cleaving TNF from its inactive to active form (Gearing et al Nature, 1994, 370, 555). This invention describes macrocyclic molecules that inhibit this conversion and hence the secretion of active TNF-a from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrom, post ischaemic reperfusion injury, malaria, Crohn's disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may also have a particular advantage in diseases where both mechansisms are involved.
There are several patents which disclose hydroxamate and carboxylate based MMP inhibitors.
PCT International Publication No. WO 92/213260 describes N-carboxyalkylpeptidyl compounds of general formula: ##STR1##
wherein AA is an amino acid, as inhibitors of matrix metallproteinase mediated diseases. PA1 U is selected from: --CO.sub.2 H, --CONHOH, --CONHOR.sup.11, --SH, --NH--COR.sup.11, --N(OH)COR.sup.11, --SN.sub.2 H.sub.2 R.sup.6, --SONHR.sup.6, CH.sub.2 CO.sub.2 H, PO(OH).sub.2, PO(OH)NHR.sup.6, CH.sub.2 SH, --C(O)NHOR.sup.12, --CO.sub.2 R.sup.12, and common prodrug derivatives; PA1 R.sup.1 is selected from: PA1 R.sup.2 is selected from H, --CO.sub.2 R.sup.5, --CONR.sup.6 R.sup.5, --CONR.sup.6 (OR.sup.5), -alkyl, -alkylaryl, -alkylheteroaryl, -alkylheterocyclic, -aryl, -heteroaryl or -heterocyclic which is substituted with one or more substituents selected from: PA1 R.sup.3 is selected from: PA1 Alternatively R.sup.2 and R.sup.3 can form a 3 to 8 membered saturated, unsaturated, aryl, heteroaryl or heterocyclic ring; PA1 R.sup.4 is selected from: PA1 R.sup.5 is selected from: PA1 R.sup.6 is selected from: PA1 Alternatively, R.sup.5 and R.sup.6 may form a 3 to 8 membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from --O, --NR.sup.6, --S(O)p, or an acyl group, optionally fused to an aryl ring; PA1 R.sup.7 and R.sup.8 may be selected independently from: PA1 optionally containing --O--, --S(O)p, --NR.sup.6, optionally fused to a substituted aryl ring, PA1 R.sup.9 is H, alkyl, cycloalkyl 5 or 6 membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with --OH, --O--(C.sub.1 -C.sub.6)alkyl, --O-acyl-alkyl, NHR.sup.10, or aryl; PA1 R.sup.10 is H or an optionally substituted alkyl group; PA1 R.sup.11 is hydrogen, alkyl of from 1 to 10 C atoms which include branched, cyclic and unsaturated alkyl groups, substituted alkyl PA1 wherein the substituent is selected from: PA1 wherein the substituent is selected from: PA1 R.sub.11a is H, --SO.sub.2 --C.sub.1 -C.sub.6 -alkyl, --SO.sub.2 --C.sub.1 -C.sub.6 -alkyl-substituted aryl, --SO.sub.2 -aryl, --SO.sub.2 -substituted heteroaryl, --COR.sup.9, --CO.sub.2 t-Bu, --CO.sub.2 Bn, or -alkyl-substituted aryl PA1 wherein the substituent is selected from: PA1 R.sup.12 is selected from: H, aryl, (C.sub.1 to C.sub.10)alkyl-, aryl (C.sub.1 to C.sub.6)alkyl-, PA1 aryloxycarbonyl, aryloxycarbonyloxy(C.sub.1 to C.sub.6 alkyl)-, arylcarbonyloxy(C.sub.1 to C.sub.6 alkyl)-, PA1 (R.sup.17)(R.sup.17a)N--(C.sub.1 -C.sub.10 alkyl)--, --CH(R.sup.13)OC(.dbd.O)R.sup.14, --CH(R.sup.13)OC(.dbd.O)OR.sup.15, or ##STR8## PA1 wherein PA1 R.sup.13 is H or C.sub.1 -C.sub.4 linear alkyl; PA1 R.sup.14 is selected from: PA1 R.sup.15 is selected from: PA1 R.sup.16 is C.sub.1 -C.sub.4 alkyl, benzyl, or phenyl, PA1 R.sup.17 and R.sup.17a is independently selected from: H, C.sub.1 -C.sub.10 alkyl,C.sub.2 -C.sub.6 alkenyl, C.sub.4 -C.sub.11 cycloalkylalkyl, and aryl(C.sub.1 -C.sub.6 alkyl); PA1 A can be absent, --(CHR.sup.6).sub.m --, --O(CHR.sup.6).sub.m --, --NR.sup.6 (CHR.sup.6).sub.m --, --S(O)p(CHR.sup.6).sub.m --, or selected from an alkyl from 1 to 10 carbon atoms which include branched, cyclic and unsaturated alkyl groups or --(C.sub.1 -C.sub.6)alkyl-aryl; PA1 B can be a bond or selected from --NH--, --NR.sup.11 --, --NR.sup.11a -- --O--, --S(O)p-(C.sub.1 -C.sub.6)alkyl-NH--(C.sub.1 -C.sub.6)alkyl-, (C.sub.1 -C.sub.6)alkyl-NR.sup.11 --(C.sub.1 -C.sub.6)alky-, --C.sub.1 -C.sub.6 --NH-aryl-, --O--(C.sub.1 -C.sub.6)alkyl-, --(C.sub.1 -C.sub.6)alkyl-O-aryl-, --S--(C.sub.1 -C.sub.6)alkyl-, --(C.sub.1 -C.sub.6)alkyl-S-aryl-, --(C.sub.1 -C.sub.6)alkyl-, --(C.sub.1 -C.sub.6)alkenyl-, --(C.sub.1 -C.sub.6)alkynyl-, --CONH--, --CONR.sup.11, --NHCO--, --NR.sup.11 CO--, --OCO--, --COO--, --OCO.sub.2 --R.sup.11 NCONR.sup.11 --, HNCONH--, --OCONR.sup.11 --, --NR.sup.11 COO--, --HNSO.sub.2 --, --SO.sub.2 NH--, aryl, cycloalkyl, heterocycloalkyl, --R.sup.11 NCSNR.sup.11 --, --HNCSNH, --OCSNR.sup.11 --, --NR.sup.11 CSO--, --HNCNNH--, and a peptide bond mimic; ##STR9## PA1 D can be absent or an alkyl from 1 to 10 carbon atoms optionally containing O, S or NR.sup.6, which include branched and cyclic and unsaturated alkyl groups and aryl C.sub.1 -C.sub.6 alkyl-; PA1 p can be 0, 1 or 2; PA1 m is an integer from 0 to 5; PA1 n is an integer from 1 to 5; PA1 W is --O--, --S(O)p- or --NR.sup.10 --; PA1 Y is selected from: --CONR.sup.10 --, --NR.sup.10 CO--, --SO.sub.2 NR.sup.10 --, --NR.sup.10 SO.sub.2 --, a peptide bond mimic, a 5 membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N,O or S, PA1 X is selected from CH.sub.2, NH, NR.sup.5, S(O)p, or O; PA1 U, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.11a R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 R.sup.17 R.sup.17a and p, m, n, A, B, D and W are as specified previously in Formula I and defined as stable compounds; PA1 U is selected from; --CO.sub.2 H, --CONHOH, --CONHOR.sup.11, --SH, --NH--COR.sup.11, --N(OH)COR.sup.11, --SN.sub.2 H.sub.2 R.sup.6, --SONHR.sup.6, CH.sub.2 CO.sub.2 H, PO(OH).sub.2, PO(OH)NHR.sup.6, CH.sub.2 SH, and common prodrug derivatives --C(O)NHOR.sup.12 and --CO.sub.2 R.sup.12 ; PA1 Z is selected from: N or CH; PA1 R.sup.1, R.sup.4, R.sup.6, R.sup.11, R.sup.11a, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17 R.sup.17a, A, B, C, are as specified previously in Formula I and defined as stable compounds; PA1 U is selected from; --CONHOH, --CONHOR.sup.11, N(OH)COR.sup.11, --SN.sub.2 H.sub.2 R.sup.6, --SONHR.sup.6, --CO.sub.2 H, --CH.sub.2 SH, --C(O)NHOR.sup.12 ; and common prodrug derivatives; PA1 R.sup.1 is selected from: PA1 R.sup.2 is selected from H, --CO.sub.2 R.sup.5, --CONR.sup.6 R.sup.5, --CONR.sup.6 (OR.sup.5), -alkyl, -alkylaryl, -alkylheteroaryl, -alkylheterocyclic, -aryl, -heteroaryl or -heterocyclic which is substituted with one or more substituents selected from: PA1 R.sup.3 is selected from PA1 Alternatively R.sup.2 and R.sup.3 can form a 3 to 6 membered saturated, unsaturated, aryl, heteroaryl or heterocyclic ring; PA1 R.sup.4 is selected from: PA1 R.sup.5 is selected from: PA1 R.sup.6 is selected from: PA1 Alternatively, R.sup.5 and R.sup.6 may form a 3 to 8 membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from --O, --NR.sup.6, --S(O)p, or an acyl group, optionally fused to an aryl ring; PA1 R.sup.7 and R.sup.8 may be selected independently from: PA1 optionally containing --O--, --S(O)p, --NR.sup.6, optionally fused to a substituted aryl ring, PA1 R.sup.9 is H, alkyl, cycloalkyl, 5 or 6 membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with --OH, --O--(C.sub.1 -C.sub.6)alkyl, --O-acyl-alkyl, NHR.sup.10, or aryl; PA1 R.sup.10 is H or an optionally substituted alkyl group; PA1 R.sup.11 is hydrogen, alkyl of from 1 to 10 C atoms which include branched, cyclic and unsaturated alkyl groups, substituted alkyl PA1 wherein the substituent is selected from: PA1 wherein the substituent is selected from: PA1 R.sup.11a is H, --SO.sub.2 --C.sub.1 -C.sub.6 -alkyl, --SO.sub.2 --C.sub.1 -C.sub.6 -alkyl-substituted aryl, --SO.sub.2 -aryl, --SO.sub.2 -substituted heteroaryl, --COR.sup.9, --CO.sub.2 t-Bu, --CO.sub.2 Bn, or -alkyl-substituted aryl PA1 wherein the substituent is selected from: PA1 R.sup.12 is selected from: H, aryl, (C.sub.1 to C.sub.10)alkyl-, aryl (C.sub.1 to C.sub.6)alkyl-, PA1 aryloxycarbonyl, aryloxycarbonyloxy(C.sub.1 to C.sub.6 alkyl)-, arylcarbonyloxy(C.sub.1 to C.sub.6 alkyl)-, PA1 (R.sup.17)(R.sup.17a)N--(C.sub.1 -C.sub.10 alkyl)-, --CH(R.sup.13)OC(.dbd.O)R.sup.14, --CH(R.sup.13)OC(.dbd.O)OR.sup.15, or ##STR13## PA1 wherein PA1 R.sup.13 is H or C.sub.1 -C.sub.4 linear alkyl; PA1 R.sup.14 is selected from: PA1 R.sup.15 is selected from: PA1 R.sup.16 is C.sub.1 -C.sub.4 alkyl, benzyl, or phenyl; PA1 R.sup.17 and R.sup.17a is independently selected from: H, C.sub.1 -C.sub.10 alkyl,C.sub.2 -C.sub.6 alkenyl, C.sub.4 -C.sub.11 cycloalkylalkyl, and aryl(C.sub.1 -C.sub.6 alkyl); PA1 A can be absent, --(CHR.sup.6).sub.m --, --O(CHR.sup.6).sub.m --, --NR.sup.6 (CHR.sup.6).sub.m --, --S(O)p(CHR.sup.6).sub.m --, or selected from an alkyl from 1 to 10 carbon atoms which include branched, cyclic and unsaturated alkyl groups or --(C.sub.1 -C.sub.6)alkyl-aryl; PA1 B can be a bond or selected from --NH--, --NR.sup.11 --, --NR.sup.11a -- --O--, --S(O)p-(C.sub.1 -C.sub.6)alkyl-NH--(C.sub.1 -C.sub.6)alkyl-, (C.sub.1 -C.sub.6)alkyl-NR.sup.11 --(C.sub.1 -C.sub.6)alky-, --C.sub.1 -C.sub.6 --NH-aryl-, --O--(C.sub.1 -C.sub.6)alkyl-, --(C.sub.1 -C.sub.6)alkyl-O-aryl-, --S--(C.sub.1 -C.sub.6)alkyl-, --(C.sub.1 -C.sub.6)alkyl-S-aryl-, --(C.sub.1 -C.sub.6)alkyl-, --(C.sub.1 -C.sub.6)alkenyl-, --(C.sub.1 -C.sub.6)alkynyl-, --CONH--, --CONR.sup.11, --NHCO--, --NR.sup.11 CO--, --OCO--, --COO--, --OCO.sub.2 --, --R.sup.11 NCONR.sup.11 --,HNCONH--, --OCONR.sup.11 --, --NR.sup.11 COO--, --HNSO.sub.2 --, --SO.sub.2 NH--, aryl, cycloalkyl, heterocycloalkyl, --R.sup.11 NCSNR.sup.11 --, --HNCSNH, --OCSNR.sup.11 --, --NR.sup.11 CSO--, --HNCNNH--, and a peptide bond mimic; ##STR14## PA1 D can be absent or an alkyl from 1 to 10 carbon atoms optionally interupted by O, S or NR.sup.6, which include branched and cyclic and unsaturated alkyl groups and --(C.sub.1 -C.sub.6)-alkyl-aryl; PA1 p can be 0, 1 or 2; PA1 m is an integer from 0 to 5; PA1 n is an integer from 1 to 5; PA1 W is --O--, --S(O)p- or --NR.sup.10 --; PA1 Y is selected from: --CONR.sup.10 --, --NR.sup.10 CO--, --SO.sub.2 NR.sup.10 --, --NR.sup.10 SO.sub.2 --, a peptide bond mimic, a 5 membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N,O or S, PA1 X is selected from CH.sub.2, NH, S and O; PA1 U, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.11a R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.17a and p, m, n, A, B, D and W are as specified previously in Formula I and defined as stable compounds; PA1 U is selected from: --CONHOH, --C(O)NHOR.sup.12, --CO.sub.2 H and common prodrug derivatives; PA1 R.sup.1 is selected from: PA1 R.sup.2 is selected from H, --CO.sub.2 R.sup.5, --CONR.sup.6 R.sup.5, --CONR.sup.6 (OR.sup.5), -alkyl, -alkylaryl, -alkylheteroaryl, -alkylheterocyclic, -aryl, -heteroaryl or -heterocyclic which is substituted with one or more substituents selected from: PA1 R.sup.3 and R.sup.4 are H; PA1 R.sup.5 is selected from: PA1 R.sup.6 is selected from: PA1 Alternatively, R.sup.5 and R.sup.6 may form a 3 to 8 membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from --O, --NR.sup.6, --S(O)p, or an acyl group, optionally fused to an aryl ring; PA1 R.sup.7 and R.sup.8 may be selected independently from: PA1 optionally containing --O--, --S(O)p, --NR.sup.6, optionally fused to a substituted aryl ring, PA1 R.sup.9 is H, alkyl, cycloalkyl, 5 or 6 membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with --OH, --O--(C.sub.1 -C.sub.6)alkyl, --O-acyl-alkyl, NHR.sup.10, or aryl; PA1 R.sup.10 is H or an optionally substituted alkyl group; PA1 R.sup.11 is hydrogen, alkyl of from 1 to 6 C atoms which include branched, cyclic and unsaturated alkyl groups, substituted alkyl; PA1 R.sup.11a is H, --SO.sub.2 --C.sub.1 -C.sub.6 -alkyl, --SO.sub.2 --C.sub.1 -C.sub.6 -alkyl-substituted aryl, --SO.sub.2 -aryl, --SO.sub.2 -substituted heteroaryl, --COR.sup.9, --CO.sub.2 t-Bu, --CO.sub.2 Bn, PA1 wherein the substituent is selected from: PA1 R.sup.12 is selected from: H, aryl, (C.sub.1 to C.sub.10)alkyl-, aryl (C.sub.1 to C.sub.6)alkyl-, PA1 (R.sup.17)(R.sup.17a)N--(C.sub.1 -C.sub.10 alkyl)-, --CH(R.sup.13)OC(.dbd.O)R.sup.14, --CH(R.sup.13)OC(.dbd.O)OR.sup.15, or ##STR17## PA1 wherein PA1 R.sup.13 is H or C.sub.1 -C.sub.4 linear alkyl; PA1 R.sup.14 is selected from: PA1 R.sup.15 is selected from: PA1 R.sup.16 is C.sub.1 -C.sub.4 alkyl, benzyl, or phenyl; PA1 R.sup.17 and R.sup.17a is independently selected from: H, C.sub.1 -C.sub.10 alkyl,C.sub.2 -C.sub.6 alkenyl, C.sub.4 -C.sub.11 cycloalkylalkyl, and aryl(C.sub.1 -C.sub.6 alkyl); PA1 A can be absent, --(CHR.sup.6).sub.m --, --O(CHR.sup.6).sub.m --, --NR.sup.6 (CHR.sup.6).sub.m --, --S(O)p(CHR.sup.6).sub.m --, or selected from an alkyl from 1 to 10 carbon atoms which include branched, cyclic and unsaturated alkyl groups or --(C.sub.1 -C.sub.6)alkyl-aryl; PA1 B can be a bond or selected from --NH--, --NR.sup.11 --, --NR.sup.11a --, --O--, --S(O)p-C.sub.1 -C.sub.6 alkyl-NH--C.sub.1 -C.sub.6 alkyl-, C.sub.1 -C.sub.6 alkyl-NR.sup.11 --C.sub.1 -C.sub.6 alky-, C.sub.1 -C.sub.6 --NH-aryl-, --O--C.sub.1 -C.sub.6 alkyl-, C.sub.1 -C.sub.6 alkyl-O-aryl-, --S--C1-C6alkyl-, C1-C6alkyl-S-aryl-, C.sub.1 -C.sub.6 alkyl-, C.sub.1 -C.sub.6 alkenyl-, C.sub.1 -C.sub.6 alkynyl-, --CONH--, --CONR.sup.11, --NHCO--, --NR.sup.11 CO--, --OCO--, --COO--, --OCO2--, --R.sup.11 NCONR.sup.11 --, HNCONH--, --OCONR.sup.11 --, --NR.sup.11 COO--, --HNSO.sub.2 --, --SO.sub.2 NH--, aryl, cycloalkyl, heterocycloalkyl, --R.sup.11 NCSNR.sup.11 --, --HNCSNH, --OCSNR.sup.11 --, --NR.sup.11 CSO--, --HNCNNH--, and a peptide bond mimic; ##STR18## PA1 D can be absent or an alkyl of from 1 to 6 carbon atoms which include branched and cyclic and unsaturated alkyl groups or --(C.sub.1 -C.sub.6)alkyl-aryl; PA1 p can be 0, 1 or 2; PA1 m is an integer from 0 to 3; PA1 n is an integer from 1 to 4; PA1 W is --O--, S(O)p or NR.sup.10 ; PA1 Y is selected from: --CONR.sup.10 --, --NR.sup.10 CO--, --SO.sub.2 NR.sup.10 --, --NR.sup.10 SO.sub.2 --, a peptide bond mimic, a 5 membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N,O or S, PA1 X is selected from CH.sub.2, NH, S and O; PA1 U is selected from; --CO.sub.2 H, --CO.sub.2 R.sup.12 and common prodrug derivatives; PA1 Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.17a and p, m, n, A, B, D and W are as specified previously in Formula I and defined as stable compounds; PA1 U is selected from: --CONHOH, --C(O)NHOR.sup.12, --CO.sub.2 H, and common prodrug derivatives; PA1 R.sup.1 is selected from: PA1 R.sup.2 is selected from H, --CO.sub.2 R.sup.5, --CONR.sup.6 R.sup.5, --CONR.sup.6 (OR.sup.5), -alkyl, -alkylaryl, -alkylheteroaryl, -alkylheterocyclic, -aryl, -heteroaryl or -heterocyclic which is substituted with one or more substituents selected from: PA1 R.sup.3 and R.sup.4 are H; PA1 R.sup.5 is selected from: PA1 R.sup.6 is selected from: PA1 Alternatively, R.sup.5 and R.sup.6 may form a 3 to 8 membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from --O, --NR.sup.6, --S(O)p, or an acyl group, optionally fused to an aryl ring; PA1 R.sup.7 and R.sup.8 may be selected independently from: PA1 optionally containing --O--, --S(O)p, --NR.sup.6, optionally fused to a substituted aryl ring, PA1 R.sup.9 is H, alkyl, cycloalkyl, 5 or 6 membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with --OH, --O--(C.sub.1 -C.sub.6)alkyl, --O-acyl-alkyl, NHR.sup.10, or aryl; PA1 R.sup.10 is H or an optionally substituted alkyl group; PA1 R.sup.11 is hydrogen, alkyl of from 1 to 6 C atoms which include branched, cyclic and unsaturated alkyl groups, substituted lower alkyl; PA1 R.sup.11a is H, --SO.sub.2 --(C.sub.1 -C.sub.6)alkyl, --SO.sub.2 --(C.sub.1 -C.sub.6)alkyl substituted aryl, --SO.sub.2 -aryl, --SO.sub.2 -substituted heteroaryl, --COR.sup.9, --CO.sub.2 t--Bu, --CO.sub.2 Bn, PA1 R.sup.12 is selected from: H, aryl, (C.sub.1 to C.sub.10)alkyl-, aryl --(C.sub.1 to C.sub.6)alkyl, PA1 (R.sup.17)(R.sup.17a)N-(C.sub.1 -C.sub.10 alkyl)-, --CH(R.sup.13)OC(.dbd.O)R.sup.14, --CH(R.sup.13)OC(.dbd.O)OR.sup.15, or ##STR21## PA1 wherein PA1 R.sup.13 is H or C.sub.1 -C.sub.4 linear alkyl; PA1 R.sup.14 is selected from: PA1 R.sup.15 is selected from: PA1 R.sup.16 is C.sub.1 -C.sub.4 alkyl, benzyl, or phenyl; PA1 A can be; --(CH.sub.2).sub.m --, --O--(CH.sub.2).sub.m --, --S--(CH.sub.2).sub.m --, --NR.sup.6 --(CH.sub.2).sub.m --; PA1 B can be a bond or selected from --NH--, --NR.sup.11 --, --NR.sup.11a --, --O--, --S(O)p-C.sub.1 -C.sub.6 alkyl-NH--C.sub.1 -C.sub.6 alkyl-, C.sub.1 -C.sub.6 alkyl-NR.sup.11 --C.sub.1 -C.sub.6 alky-, C.sub.1 -C.sub.6 --NH-aryl-, --O--C.sub.1 -C.sub.6 alkyl-, C.sub.1 -C.sub.6 alkyl-O-aryl-, --S--C1-C6alkyl-, C1-C6alkyl-S-aryl-, C.sub.1 -C.sub.6 alkyl-, C.sub.1 -C.sub.6 alkenyl-, C.sub.1 -C.sub.6 alkynyl-, --CONH--, --CONR.sup.11, --NHCO--, --NR.sup.11 CO--, --OCO--, --COO--, --OCO2--, --R.sup.11 NCONR.sup.11 --, HNCONH--, --OCONR.sup.11 --, --NR.sup.11 COO--, --HNSO.sub.2 --, --SO.sub.2 NH--, aryl, cycloalkyl, heterocycloalkyl, --R.sup.11 NCSNR.sup.11 --, --HNCSNH, --OCSNR.sup.11 --, --NR.sup.11 CSO--, --HNCNNH--, and a peptide bond mimic; ##STR22## PA1 D is --(CH.sub.2)m--; PA1 p can be 0, 1 or 2; PA1 m is an integer from 0 to 3; PA1 n is an integer from 1 to 4; PA1 W is --O--, S(O)p or NR.sup.10 ; PA1 Y is selected from: --CONR.sup.10 --, --NR.sup.10 CO--, --SO.sub.2 NR.sup.10 --, --NR.sup.10 SO.sub.2 --, a peptide bond mimic, a 5 membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N,O or S, PA1 R.sup.1 is selected from: PA1 R.sup.2 is selected from H, --CO.sub.2 R.sup.5, --CONR.sup.6 R.sup.5, --CONR.sup.6 (OR.sup.5), -alkyl, -alkylaryl, -alkylheteroaryl, -alkylheterocyclic, -aryl, -heteroaryl or -heterocyclic which is substituted with one or more substituents selected from: PA1 R.sup.5 is selected from: PA1 R.sup.6 is selected from: PA1 Alternatively, R.sup.5 and R.sup.6 may form a 3 to 8 membered ring optionally unsaturated containing from 1 to 3 heteroatoms selected from --O, --NR.sup.6, --S(O)p, or an acyl group, optionally fused to an aryl ring; PA1 R.sup.7 and R.sup.8 may be selected independently from: PA1 optionally containing --O--, --S(O)p, --NR.sup.6, optionally fused to a substituted aryl ring, PA1 R.sup.9 is H, alkyl, cycloalkyl, 5 or 6 membered ring optionally containing from 1 to 2 N, O or S(O)p, optionally substituted with --OH, --O--(C.sub.1 -C.sub.6)alkyl, --O-acyl-alkyl, NHR.sup.10, or aryl; PA1 R.sup.10 is H or an optionally substituted alkyl group; PA1 R.sup.11 is hydrogen, alkyl of from 1 to 6 C atoms which include branched, cyclic and unsaturated alkyl groups, substituted lower alkyl; PA1 R.sup.11a is H, --SO.sub.2 --(C.sub.1 -C.sub.6)alkyl, --SO.sub.2 --(C.sub.1 -C.sub.6)alkyl substituted aryl, --SO.sub.2 -aryl, --SO.sub.2 -substituted heteroaryl, --COR.sup.9, --CO.sub.2 t-Bu, --CO.sub.2 Bn, PA1 m is an integer from 0 to 5; PA1 n is an integer from 1 to 5; PA1 p can be 0, or 2; PA1 W is --O--, S(O)p or NR.sup.10 ; PA1 Z is CH.sub.2 or O PA1 Y is selected from: --CONR.sup.10 --, --NR.sup.10 CO--, --SO.sub.2 NR.sup.10 --, --NR.sup.10 SO.sub.2 --, a peptide bond mimic, a 5 membered heterocyclic ring saturated, unsaturated or partially unsaturated containing from 1 to 4 heteroatoms selected from N,O or S,
PCT International Publication No. WO 90/05716 discloses hydroxamic acid based collagenase inhibitors having the general formula: ##STR2##
PCT International Publication No. WO 92/13831 describes related hydroxamic acids having collagenase inhibiting activity with the general formula: ##STR3##
PCT International Publication No. WO 94/02446 discloses metaloproteinase inhibitors which are natural amino acid derivatives of general formula: ##STR4##
WO95/0984.sub.1 d e scribes compounds that are hydroxamic acid derivatives and are inhibitors of cytokine production. ##STR5##
European Patent Application Publication No. 574,758 A1, discloses hydroxamic acid derivatives as collagenase inhibitors having the general formula: ##STR6##
GB 2 268 934 A and WO 94/24140 claim hydroxamate inhibitors of MMPs as inhibitors of TNF production.
The compounds of the current invention act as inhibitors of MMPs, in particular aggrecanase and TNF-C, thereby preventing cartilage loss and destruction and inflammatory disorders involving TNF. The hydroxamic and carboxylic acids and derivatives are cyclic, and thus non-peptide in nature, which offers a distinct advantage over existing inhibitors because they have superior pharmacokinetic parameters. A selection of these molecules are water soluble and are orally bioavailable.